US4321194A - N-Substituted aziridine-2-carboxylic acid derivatives for immuno stimulation - Google Patents

N-Substituted aziridine-2-carboxylic acid derivatives for immuno stimulation Download PDF

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US4321194A
US4321194A US06/059,863 US5986379A US4321194A US 4321194 A US4321194 A US 4321194A US 5986379 A US5986379 A US 5986379A US 4321194 A US4321194 A US 4321194A
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radical
aziridine
cyano
carboxylic
phenyl
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Elmar Bosies
Herbert Berger
Wolfgang Kampe
Uwe Bicker
Alfred Grafe
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Roche Diagnostics GmbH
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Boehringer Mannheim GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants

Definitions

  • the present invention is concerned with pharmaceutical compositions containing N-substituted aziridine-2-carboxylic acid derivatives, some of which are new, and with the preparation of such N-substituted aziridine-2-carboxylic acid derivatives.
  • aziridines because of their structure and properties, belong to the alkylating-acting compounds, for example cyclophosphamide compounds, which play an important part in the therapy of cancer.
  • the alkylating action does not take place selectively with the components of the cancer cells so that these compounds can also act cancerogenically on normal cells.
  • substitution with a cyano group in the 2-position of the aziridine rings showed that the ability to alkylate and thus also the toxicity was lost.
  • German Democratic Republic Patent Specification No. 110,492 describes 1-carbamoyl-2-cyanoaziridine which, when administered intraveneously to rats, bring about a very marked increase of the leukocytes and lymphocytes, whereas the number of erythrocytes remains almost unchanged. Furthermore, a considerable multiplication of the antibody-forming spleen cells was observed. Therefore, this compound can be used as an immune-stimulating thereapeutic in cases of bacterial and viral infections (see Federal Republic of Germany Patent Specification No. 25 28 460.0). However, the low stability of this compound in solution and the complete ineffectiveness when administered orally proved to be serious disadvantages of this compound.
  • the present invention also provides pharmaceutical compositions which, in addition to containing at least one compound of general formula (I) and an appropriate carrier, also contain at least one known chemotherapeutic agent.
  • a chemotherapeutic agent is generally to be understood to be a substance with an antimicrobial action, for example a penicillin or cephalosporin compound, as well as a compound of the nitrofuran group.
  • the synergistic effect is shown, for example, in the case of a pharmaceutical combination which contains an immune stimulant compound of general formula (I) and the bacteriostatically-acting chemotherapeutic compound chloramphenicol.
  • the present invention includes within its scope all stereoisomeric compounds of general formula (I) which, for example, exist because of asymmetric carbon atoms or of cis-trans isomerism, the separation of which into the stereoisomeric forms can be carried out by known processes.
  • alkyl if not stated otherwise, is to be understood to mean, alone or in combination, for example in alkoxy, alkoxycarbonyl, N-alkylamino, alkylthio, alkylsulphinyl and alkylsulphonyl radicals, a straight-chained or branched chain containing up to 8 carbon atoms.
  • Preferred alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, n-pentyl, neo-pentyl and n-hexyl radicals.
  • the alkyl chain can optionally be substituted by, for example, halogen, such as chlorine, or by hydroxyl, nitro or cyano.
  • Further substituents which can be present include amino groups, preferably dimethylamino and 2-cyanoaziridin-1-yl radicals, acylamino radicals, for example, formamido, acetamido and benzamido radicals, and carbamoyl, carbalkoxy and alkoxy radicals.
  • the mono- and poly-unsaturated aliphatic hydrocarbon radicals are to be understood to be radicals which contain 3 to 8 and preferably 3 to 5 carbon atoms, with at least one double and/or triple bond in any desired position of the unsaturated chain, preferred radicals of this type including the vinyl, allyl, methallyl, crotyl, 2-methylpropenyl, propargyl, but-2-ynyl, but-3-ynyl and pent-3-enyl radicals.
  • cycloalkyl and cycloalkenyl radicals are to be understood to be those containing 3 to 10 carbon atoms, especially the cyclopropyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptenyl and 3,6-dioxo-1,4-cyclohexadienyl radicals, as well as cycloalkyl radicals bridged with 1 to 3 carbon atoms, for example the norbornyl and adamantyl radicals.
  • cycloalkyl and cycloalkenyl radicals interrupted by hetero atoms are preferably the tetrahydrofuryl, tetrahydropyranyl, thienyl, optionally substituted piperidinyl, morpholinyl and pyrrolidinyl radicals, as well as the N-methyl-3,4-dehydropiperidinyl and the N-methyl-piperazinyl radicals.
  • aryl radicals alone or in combination, for example in aryloxy and arylthio radicals, are aromatic carbocyclic radicals and preferably phenyl, naphthyl, anthracenyl, phenanthrenyl and fluorenyl radicals.
  • hetaryl radicals there are to be understood aromatic ring systems containing 5 or 6 members and one or more hetero atoms, for example, oxygen, sulphur or alkylated or acylated nitrogen, which can also be condensed with one or two benzene rings or with another heterocycle.
  • Preferred radicals of this type include the pyridyl, quinolyl, furyl, thienyl, benzofuryl, imidazolyl, pyrazolyl, thiazolyl, pyrimidinyl, pyridazinyl, s-triazolyl, s-triazinyl and purinyl radicals.
  • halogen atoms are to be understood to be fluorine, chlorine and bromine atoms.
  • acyl radicals there are to be understood, alone or in combination, for example in acyloxy radicals, the acid residues of organic carboxylic and sulphonic acids, preferred radicals of this type including the formyl, acetyl, benzoyl, furoyl, tosyl and methanesulphonyl radicals.
  • aryl and hetaryl radicals can be substituted one or more times by the above-mentioned substituents.
  • X is a carbamoyl group, it can be optionally substituted by lower alkyl, cycloalkyl, aryl and acyl radicals.
  • the present invention also provides new compounds of the general formula: ##STR3## wherein X is a carboxy or nitrile group or an alkoxycarbonyl radical or an unsubstituted or substituted carbamoyl group, R' is a straight-chained or branched, saturated or mono- or polyunsaturated aliphatic hydrocarbon radical which is optionally substituted one or more times by halogen, alkoxy, hydroxyl, dialkylamino, cycloalkylamino, acylamino, acyl, nitro, alkylthio, alkylsulphinyl, alkylsulphonyl, nitrile, carbalkoxy or carbamoyl radicals or by cycloalkyl radicals optionally substituted by alkyl, alkoxy or carbalkoxy, or by cycloalkenyl radicals, which can optionally be bridged, or by an aliphatic or aromatic heterocyclic radical, by aryl, aryloxy
  • Preferred new compounds of general formula I' according to the present invention include:
  • the compounds of general formula (I') can be prepared in known manner and preferably by one of the following methods:
  • T is a hydrogen atom or an alkyl or carboxylic acid ester group and U is an aldehyde or carboxylic acid ester group;
  • a compound obtained of general formula (I) can subsequently be converted into another compound of general formula (I) and, if desired, a compound obtained of general formula (I) can be converted into a pharmacologically-acceptable salt.
  • an epoxide of general formula (X) can be reacted with an amine of the general formula (III) and the aminoalcohol thereby obtained dehydrated, to give an aziridine derivative of general formula (I).
  • an aziridine derivative of general formula (I) for the conversion of the epoxide into an aziridine, use can also be made of compounds such as R-N-P(O)(OAlk) 2 - or Ph 3 P ⁇ N--R, wherein R has the same meaning as above, Ph is a phenyl radical and Alk is a lower alkyl radical, for example a methyl or ethyl radical (see Tetrahedron Letters, 1976, 4003 and Chem. Ber. 109, 814/1976).
  • reaction components are, as a rule, reacted without the use of a solvent at a temperature of from 0° to 60° C.
  • the reaction products possibly have to be purified by column chromatography.
  • Oxazolidinones of general formula (XIII) are, as a rule, thermolyzed without the use of a solvent in the presence of a base, for example, triethanolamine or dicyclohexylethylamine, the reaction product being removed by distillation during the thermolysis.
  • the thermolysis temperature can be from 170° to 250° C.
  • the reagent used for splitting off E-G is preferably an alcoholate, such as an alkali metal methylate or alkali metal ethylate, in the corresponding alcohol.
  • an alcoholate such as an alkali metal methylate or alkali metal ethylate
  • a tertiary amine for example, triethylamine, triethanolamine or dicyclohexylethylamine
  • a solvent for example, methanol, ethanol, benzene, toluene, diethyl ether or dioxane.
  • G and E are Hal
  • the splitting off reaction can be carried out with the use of a conventional dehalogenation agent and preferably with zinc or sodium.
  • the subsequent conversion of compounds of general formula (I) into other compounds of general formula (I) can be carried out, on the one hand, by conversion of the substituent X.
  • a compound in which X is an alkoxycarbonyl radical can be converted, by reaction with ammonia, into a compound in which X is a carbamoyl group which, in turn, can be converted with a dehydration agent into a compound in which X is a nitrile group.
  • the conversion of an ester group into an amide group can be carried out with gaseous ammonia in an organic solvent, preferably in methanol or ethanol, or with aqueous ammonia at a temperature of from 0° to 25° C.
  • the desired amide either precipitates out or can be isolated from the reaction mixture by, for example, column chromatography.
  • a carbamoyl group can be converted into a nitrile group by using a dehydration agent known from the literature and preferably with a mixture of triphenylphosphine, carbon tetrachloride and triethylamine.
  • the solvent usually employed is a halogenated hydrocarbon, for example methylene chloride or chloroform, but acetonitrile can also be used.
  • the desired nitrile is isolated from the reaction mixture by distillation.
  • the 2-alkoxycarbonyl-, 2-carbamoyl- and 2-cyanoaziridine derivatives are usually converted into 2-carboxyaziridines by saponification processes which are known from the literature.
  • the compounds of general formula (I) are mixed in conventional manner with appropriate pharmaceutical carrier materials, optionally granulated and pressed, for example, into tablets or dragee cores.
  • the mixture can also be filled into hard gelatine capsules.
  • appropriate adjuvants there can also be produced a solution or suspension in water, an oil, for example olive oil, or high molecular weight polymer, for example polyethylene glycol, which can then be worked up to give injection solutions, soft gelatine capsules, syrups or drops.
  • compositions are either provided with a coating which only dissolves in the alkaline medium of the small intestine or an adjuvant, such as antacid, for example magnesium oxide, which is able to neutralize the gastric juices to a pH value above 6, is incorporated into the formulation.
  • an adjuvant such as antacid, for example magnesium oxide, which is able to neutralize the gastric juices to a pH value above 6, is incorporated into the formulation.
  • solid carrier materials examples include starch, starch derivatives, sugar, sugar alcohols, celluloses and cellulose derivatives, tensides, talc, highly-dispersed silicic acids, high molecular weight fatty acids and the salts thereof, gelatine, agaragar, calcium phosphate, animal and vegetable fats and waxes and solid high molecular weight polymers, for example polyethylene glycols or polyvinylpyrrolidones. If liquid active materials are to be worked up to give tablets or hard gelatine capsules, in addition to highly-dispersed silicic acid, there can also be used carriers, such as phosphates, carbonates and oxides.
  • Compositions suitable for oral administration can, if desired, contain flavoring and/or sweetening agents.
  • compositions of general formula (I) for pharmaceutical combinations in which compounds of general formula (I) are present together with a chemotherapeutic agent, in general there are used the same galenical forms of composition as are described above for the individual substances.
  • the two active materials i.e. the immune stimulant and the chemotherapeutic agent, are usually present in the composition in a weight ratio of 10:1 to 1:10, it having proved to be advantageous to use an equimolar ratio of the two components.
  • a preferred composition comprises 100 mg. of chloramphenicol as chemotherapeutic agent and 33.3 mg. of 1-allyl-2-cyanoaziridine, together with appropriate carrier materials, such as starch, and can be produced in the form of a 250 mg. tablet which, as a rule, are taken orally twice a day.
  • mice Female adult NMRI mice (body weight 25 to 30 g.) were, on 0 day, infected with 1.0 ⁇ 10 7 micro-organisms/animal (Escherichia coli) intraperitoneally. Treatment was carried out as follows:
  • 1st Group 40 mg./kg.
  • A oral, dissolved in 0.5% tylose solution
  • 2nd Group 13.4 mg./kg.
  • B oral, dissolved in 0.5% tylose solution.
  • 3rd Group 40 mg./kg. A+13.4 mg./kg. B, oral, dissolved in 0.5% tylose solution
  • preferred compounds according to the present invention for the preparation of pharmaceutical compositions with immune-stimulating action include the following compounds:
  • Crotonitrile are mixed at ambient temperature, within the course of 2 hours, with 32 g. bromine and the solution then heated to 30° C. until decolorized.
  • the reaction mixture is diluted with 100 ml. diethyl ether and cooled to 0° C.
  • a solution of 20.2 g. triethylamine in 50 ml. diethyl ether is added dropwise thereto and the reaction mixture further stirred for 1 hour at 0° C.
  • To the suspension obtained is added at 0° C. a mixture of 20.2 g. triethylamine and 11.4 g. allylamine in 100 ml. diethyl ether and the reaction mixture stirred for 4 days at ambient temperature.
  • Triethylamine are added, with stirring, at 0° C. to 52 g. ethyl 2,3-dibromopropionate in 250 ml. toluene and, after 2 hours, a solution of 21.4 g. benzylamine in 250 ml. toluene added thereto.
  • the reaction mixture is subsequently further stirred for 3 days at ambient temperature.
  • the suspension is then shaken out several times with water and the organic phase is dried and evaporated and the residue is taken up in diethyl ether.
  • the ethereal solution is passed over 400 g. deactivated aluminum oxide and the eluate is evaporated and fractionated. There are obtained 30.7 g. (about 75% of theory) ethyl 1-benzylaziridine-2-carboxylate; b.p. 0 .03 : 98°-101° C.
  • compositions which contain compounds of general formula (I) or salts thereof.
  • the active materials and adjuvants are mixed, optionally granulated and pressed into dragee cores using conventional machines.
  • the dragee cores are then coated in the usual manner with a film which is resistant to gastric juices but is soluble in intestinal juice (for example an anionic polymer of methacrylic acid and methyl methacrylate).
  • the active material and adjuvants are mixed, optionally granulated and pressed into tablets.
  • compositions suitable for injection which contain 1-allyl-2-cyanoaziridine, there can be mentioned aqueous solutions of polyethylene glycol 400, ethylene glycol monoethyl ether and ethanol, as well as a solution of the active material in "Miglyol” 812 neutral oil, the latter adjuvant only being used for intramuscular administration.
  • the compositions are formulated in such a manner that the pH value, buffer capacity and titration basicity do not deviate very much from the physiological values.
  • These injection compositions withstand sterilization in an autoclave for 20 minutes at 121° C. without any chemical change taking place.
  • the solvents are mixed together with the active material in a kettle.
  • the solution thus obtained is sterilized by filtration through filter layers of Fibrafix AF.
  • the first 15 liters are pre-runnings which are recycled to the batch.
  • the membrane filtration is carried out directly on a filling machine via a Sartorius membrane filter of 0.2 ⁇ m. pore size.
  • the solution is subsequently filled in 5 ml. ampoules and then sterilized in an autoclave for 20 minutes at 121° C.
  • the active material can also be worked up in admixture with wax, soya bean oil, lecithin and hydrogenated fats to give a conventional soft gelatine formulation.
  • the active material can be mixed with the appropriate amounts of the above-mentioned adjuvants and worked up on a special machine to give soft gelatine capsules of various sizes and dosages.
  • the active material is mixed with appropriate amounts of the above-mentioned adjuvants.
  • the mixture is sterilized by means of filter layers of Fibrafix AF and also filtered through membrane filters with a pore size of 0.2 ⁇ m., followed by filling into 20 ml. drop bottles or into 200 ml. syrup bottles.
  • the present invention also provides pharmaceutical compositions comprising the new compound and/or at least one solid or liquid pharmaceutical diluent or carrier.
  • an N-substituted aziridine-2-carboxylic acid derivative the invention is mixed in known manner with an appropriate pharmaceutical carrier substance and formed, for example, into tablets or dragees or, with the addition of appropriate adjuvants, suspended or dissolved in water or an oil, for example olive oil, and placed in capsules.
  • the active material is acid labile
  • the composition is provided with a coating which only dissolves in the alkaline medium of the intestines or an appropriate carrier material, for example a high molecular weight fatty acid or carboxymethyl-cellulose is mixed therewith.
  • solid carrier materials include starch, lactose, mannitol, methyl cellulose, talc, highly dispersed silicic acids, high molecular weight fatty acids (for example stearic acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular weight poylmers (such as polyethylene glycols).
  • Compositions suitable for oral administration can, if desired, contain flavoring and/or sweetening materials.
  • the active material is preferably injected.
  • injection medium it is preferred to use water which contains the additives usual in the case of injection solutions, such as stabilizing agents, solubilizing agents and/or weakly alkaline buffers.
  • Additives of this type include, for example, phosphate and carbonate buffers, ethanol, complex-forming agents (for example ethylenediamine-tetraacetic acid and the non-toxic salts thereof) and high molecular weight polymers (for example liquid polyethylene oxide) for viscosity regulation.
  • the active material may be applied one or more times with each dose containing about 25 to 3000 and preferably 50 to 500 mg of active material.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
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  • Medicinal Chemistry (AREA)
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  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
US06/059,863 1978-08-03 1979-07-23 N-Substituted aziridine-2-carboxylic acid derivatives for immuno stimulation Expired - Lifetime US4321194A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE2833986 1978-08-03
DE19782833986 DE2833986A1 (de) 1978-08-03 1978-08-03 Immunstimulierende n-substituierte aziridin-2-carbonsaeurederivate, verfahren zu ihrer herstellung sowie arzneimittel, die diese substanzen enthalten

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US06/268,964 Division US4409236A (en) 1978-08-03 1981-06-01 N-Substituted aziridine-2-carboxylic acid derivatives and immuno-stimulation composition and method
US06/334,614 Continuation-In-Part US4410532A (en) 1978-08-03 1981-12-28 N-Substituted aziridine-2-carboxylic acid derivatives and their immuno-stimulation compositions and methods

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US06/059,863 Expired - Lifetime US4321194A (en) 1978-08-03 1979-07-23 N-Substituted aziridine-2-carboxylic acid derivatives for immuno stimulation
US06/268,964 Expired - Fee Related US4409236A (en) 1978-08-03 1981-06-01 N-Substituted aziridine-2-carboxylic acid derivatives and immuno-stimulation composition and method
US06/334,614 Expired - Fee Related US4410532A (en) 1978-08-03 1981-12-28 N-Substituted aziridine-2-carboxylic acid derivatives and their immuno-stimulation compositions and methods

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US06/334,614 Expired - Fee Related US4410532A (en) 1978-08-03 1981-12-28 N-Substituted aziridine-2-carboxylic acid derivatives and their immuno-stimulation compositions and methods

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Cited By (6)

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US4826858A (en) * 1984-12-21 1989-05-02 Boehringer Mannheim Gmbh N-substituted aziridine-2-carboxylic acid derivatives, processes for the preparation thereof and pharmaceutical compositions containing them
US4925835A (en) * 1986-05-01 1990-05-15 Sloan-Kettering Institute For Cancer Research Aziridinyl putrescine containing compositions and their uses in treating prostate cancer
KR19980083844A (ko) * 1997-05-19 1998-12-05 이웅열 새로운 아지리딘 유도체 및 그 제조방법
WO2002041871A3 (en) * 2000-11-21 2003-04-17 Univ Texas Composition comprising an imexon or derivatives thereof and lipids
US20030119827A1 (en) * 2001-06-08 2003-06-26 Boehringer Ingelheim Pharmaceuticals, Inc. Novel nitriles useful as reversible inhibitors of cysteine proteases
US20030129222A1 (en) * 2000-11-21 2003-07-10 Gabriel Lopez-Berestein Liposomal imexon

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JPS6287512A (ja) * 1985-10-11 1987-04-22 ベ−リンガ−・マンハイム・ゲゼルシヤフト・ミツト・ベシユレンクテル・ハフツング 選択的免疫抑制剤
FR2776292B1 (fr) * 1998-03-20 2004-09-10 Oncopharm Cephalotaxanes porteurs de chaine laterale et leur procede de synthese
KR20010000195A (ko) * 2000-08-10 2001-01-05 하현준 (2ｒ)- 및 (2ｓ)-아지리딘-2-카르복실산 에스테르 및(2ｒ)- 및 (2ｓ)-2-히드록시메틸 아지리딘 제조 방법

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4826858A (en) * 1984-12-21 1989-05-02 Boehringer Mannheim Gmbh N-substituted aziridine-2-carboxylic acid derivatives, processes for the preparation thereof and pharmaceutical compositions containing them
US4925835A (en) * 1986-05-01 1990-05-15 Sloan-Kettering Institute For Cancer Research Aziridinyl putrescine containing compositions and their uses in treating prostate cancer
KR19980083844A (ko) * 1997-05-19 1998-12-05 이웅열 새로운 아지리딘 유도체 및 그 제조방법
WO2002041871A3 (en) * 2000-11-21 2003-04-17 Univ Texas Composition comprising an imexon or derivatives thereof and lipids
US20030129222A1 (en) * 2000-11-21 2003-07-10 Gabriel Lopez-Berestein Liposomal imexon
US20030119827A1 (en) * 2001-06-08 2003-06-26 Boehringer Ingelheim Pharmaceuticals, Inc. Novel nitriles useful as reversible inhibitors of cysteine proteases
US6982263B2 (en) 2001-06-08 2006-01-03 Boehringer Ingelheim Pharmaceuticals, Inc. Nitriles useful as reversible inhibitors of cysteine proteases

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GB2026863A (en) 1980-02-13
US4410532A (en) 1983-10-18
FI70570C (fi) 1986-09-24
IT7924769A0 (it) 1979-07-30
YU41169B (en) 1986-12-31
NO792545L (no) 1980-02-05
FI792393A7 (fi) 1980-02-04
DE2833986A1 (de) 1980-02-21
PL126531B1 (en) 1983-08-31
FR2432317B1 (enrdf_load_stackoverflow) 1983-03-18
GB2106896A (en) 1983-04-20
CH645540A5 (de) 1984-10-15
NO152413C (no) 1985-09-25
SU1145927A3 (ru) 1985-03-15
CS227301B2 (en) 1984-04-16
OA06310A (fr) 1981-06-30
YU188179A (en) 1983-06-30
NL7905855A (nl) 1980-02-05
PH19007A (en) 1985-12-03
JPH0257523B2 (enrdf_load_stackoverflow) 1990-12-05
MY8600045A (en) 1986-12-31
ZA793966B (en) 1980-08-27
DD145267A5 (de) 1980-12-03
SG85784G (en) 1985-06-07
IL57939A0 (en) 1979-11-30
SE445552B (sv) 1986-06-30
BE878020A (fr) 1980-02-01
AU524572B2 (en) 1982-09-23
CA1142530A (en) 1983-03-08
ATA531479A (de) 1985-05-15
PT70009A (de) 1979-08-01
AU4930879A (en) 1980-02-07
DK156431C (da) 1990-01-22
KR830000902A (ko) 1983-04-28
AR228945A1 (es) 1983-05-13
FR2432317A1 (fr) 1980-02-29
US4409236A (en) 1983-10-11
NZ191169A (en) 1981-01-23
IL57939A (en) 1985-02-28
SE7906461L (sv) 1980-02-04
FR2445316B1 (enrdf_load_stackoverflow) 1983-07-29
GR74424B (enrdf_load_stackoverflow) 1984-06-28
HU184610B (en) 1984-09-28
IE48462B1 (en) 1985-01-23
DK320379A (da) 1980-02-04
JPS5522694A (en) 1980-02-18
NO152413B (no) 1985-06-17
EG14369A (en) 1983-12-31
GB2106896B (en) 1983-08-17
FR2445316A1 (fr) 1980-07-25
DK156431B (da) 1989-08-21
KE3493A (en) 1985-02-01
PL217527A1 (enrdf_load_stackoverflow) 1980-07-01
LU81563A1 (de) 1980-08-08
HK13285A (en) 1985-03-01
IT1123503B (it) 1986-04-30
KR860000320B1 (ko) 1986-04-09
JPS6243991B2 (enrdf_load_stackoverflow) 1987-09-17
GB2026863B (en) 1983-03-30
JPS63258415A (ja) 1988-10-25
NL187239C (nl) 1991-07-16
AT379382B (de) 1985-12-27
IE791478L (en) 1980-02-03
DE2833986C2 (enrdf_load_stackoverflow) 1988-04-07
ES483116A1 (es) 1980-04-16
FI70570B (fi) 1986-06-06

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